Current methods of designing and producing organ simulants, organ assist devices or organ replacements include the use of transplanted organs from donor humans, transplanted organs from animals (i.e., xenografts), bioartificial mechanical devices and tissue-engineered organs.
Tissue-engineered organs have historically been attempted through the use of cell-seeded constructs. Initially, tissue engineered constructs were built using solid freeform fabrication technology, however, elements on the size scale of capillaries could not be built. Subsequent approaches to designing and building tissue engineered constructs entailed a microfabrication approach, which enabled the generation of two-dimensional microfluidic networks capable of simulating many features of human physiology, including the distribution of parameters such as vessel sizes, lengths and densities. Importantly, the microfabrication approach enabled capillary-sized features to be built. In the case of blood vessels, distribution of these parameters regulates important components of vascular function, including blood pressure, blood cell velocity, wall shear stress, hematocrit distribution, and the maximum distance between capillaries (which is limited by the diffusivity of oxygen in the tissue).
Once the two-dimensional microfluidic networks were designed, polymer scaffolds based on replica molding technology were constructed, and integrated into a three-dimensional architecture by folding, stacking or rolling the two dimensional sheets into a three dimensional configuration with large vertical inlet and outlet tubes linking the two dimensional networks. However, with this method, distribution of vessel network sizes is limited in three-dimensional integration. Branching networks are not truly three-dimensional, and vessels larger than the capillaries take up a large amount of available space within the two dimensional networks. This restraint imposes a limitation on the available space for small blood vessels, and as a result, the tissue engineered constructs suffer from non-physiological pressures and fluid velocities. If a larger number of the mid-sized vessels could be arranged vertically, more room in the two-dimensional networks could be made available for capillaries.
In true physiological blood vessel networks, 85% of the total cross-section of vessels lies in the smallest vessels, the capillaries (Guyton and Hall, Textbook of Medical Physiology, 10th Ed., W. B. Saunders (2000)). The human body utilizes the three-dimensional fractal branching nature of the vasculature to incorporate a large number of small vessels (Kaazempur-Mofrad et al., Annals of Biomedical Engineering, 29,154 (2001). This weighting of vessel distribution is necessary because the capillaries are performing the most crucial functions of the vasculature, namely, oxygen, nutrient and waste transport. All larger vessels are simply channels for the distribution of blood to and from the organs. According to morphometric models of the vascular system, vessels are organized into categories, or families, of sizes and this categorization allows for the characterization of a mathematical distribution of vessels upon which models for the networks may be developed (Bassingthwaighte et al., Fractal Physiology (Oxford, Oxford University Press, 1994); Kassab and Fung, Am J Physiol 267, H319 (1994); Pries et al., Am J Physiol 272, H2716 (1997); Fenton et al., Microvasc Res 29, 103 (1985); Pries et al., Am J Physiol 263, H1770 (1992); Kiani et al., Am J Physiol 266, H1822 (1994); Lipowsky et al., Microvasc Res 19, 297 (1980); Fung, Biodynamics: Circulation. (New York, Springer, 1984)). Improved three-dimensional models and designs that provide higher cell densities and a larger relative number of small vessels would contribute to enhanced methods and devices for tissue engineering.